Targeted delivery of botulinum toxin to the sphenopalatine ganglion

ABSTRACT

Botulinum toxin, among other presynaptic neurotoxins is used for the treatment and prevention of migraine and other headaches associated with vascular disorders. Presynaptic neurotoxins are delivered focally, targeting the sphenopalatine ganglion. Exemplary delivery is carried out by way of injection.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of application Ser. No. 13/158,894,filed Jun. 13, 2011, now U.S. Pat. No. 8,530,425, which is acontinuation of application Ser. No. 12/136,503, filed Jun. 10, 2008,now U.S. Pat. No. 7,749,515, which is a continuation-in-part ofapplication Ser. No. 11/296,079, filed Dec. 7, 2005, now U.S. Pat. No.7,655,244, which claims the benefit of and priority to U.S. ProvisionalApplication No. 60/593,641, filed Feb. 1, 2005, the entire contents ofeach are herein incorporated by reference in their entireties.

FIELD OF THE INVENTION

The present invention generally relates to the use of botulinum toxin totreat pain, rhinorrhea or excessive lacrimation by targeting ganglion,such as the sphenopalatine ganglion, for example.

BACKGROUND OF THE INVENTION

Migraine is a primary headache disorder that may be characterized byunilateral throbbing pain which worsens with head movement. This can beassociated with other symptoms including nausea, light and noisesensitivity, lacrimation, nasal congestion, and rhinorrhea. An array offactors can trigger migraine headache, such as internal changes(hormonal changes, stress, sleep deprivation) or external changes(weather changes, alcohol, flickering light).

In some cases, a migraine attack begins with a premonitory visual aura.These patients experience a visual disturbance in the form of a zigzagspectrum around a blind spot, which grows in size over a 20-30 minperiod. This visual effect is known as the “fortification spectrum.” Thedevelopment of the fortification spectrum over time has been shown tocorrespond to a wave of depression in the activity of cortical neurons,which typically begins in the occipital lobe, and spreads anteriorly.The establishment of this correspondence has permitted the elaborationof a theory about the pathophysiological changes that may cause migraineand other headaches.

As neurons depress, they release nitric oxide (NO), which triggers thedilation of meningeal blood vessels. This vasodilation can result in adull headache, which corresponds to the earliest phase of migraine.

The dilation of the meningeal blood vessels increases the activity ofthe nerve endings of the primary afferent neurons of the trigeminalnerve that are wrapped around them. As a result, the trigeminal cellsrelease calcitonin gene related protein (CGRP), a vasodilatorneuropeptide which further increases the dilation of the meningeal bloodvessels, and further feeds into the trigeminal nerve activation. Thelocal intracranial increased activation of the trigeminal nerve spreadsthrough the trigeminal ganglion into the Trigeminal Nucleus Caudalis(TNC) in the brainstem in a process known as peripheral sensitization.The activation of the TNC leads in turn to a central activation process,through its thalamic and cortical projections, which are illustrated inFIG. 1.

Although the pain associated with migraine involves input from meningealarteries, activation of the TNC may result in referred pain anywherealong the trigeminal network, including the temporal arteries andtemporal muscles. The trigeminocervical network involved in thepathophysiology of migraine contains the three main branches of thetrigeminal nerve: the ophthalmic branch (V1), the maxillary branch (V2),and the mandibular branch (V3), as illustrated in FIG. 2; as well as thesensory nerves for the posterior head and neck (C2, C3, C4, C5) thatfeed into the TNC. A detailed anatomical map of the relevant pathwayscan be found in pages 316, 317, 600, 601 and 736 of Agur, A. M. R. andDalley II, A. F. (2005) Atlas of Anatomy 11^(th) Ed., LippincottWilliams & Wilkins, Philadelphia, which is hereby incorporated byreference.

The activation of the TNC in the brainstem can further spread to theoccipital nerve by virtue of its anatomical connection to the TNC,leading to pain sensation in the occipital area.

The activation of the TNC can also spread to the parasympathetic system,by activation of a nearby nucleus in the brainstem, the SuperiorSalivatory Nucleus (SSN), which is connected to the nucleus caudalisthrough a network of interneurons, as shown in FIG. 3.

Neurons from the SSN synapse with the Sphenopalatine ganglion, whichprovides vasomotor innervation to blood vessels and secretomotorinnervation to the lacrimal glands, nasal and sinus mucosa. When theparasympathetic system is activated, the upper respiratory tractsymptoms associated with migraine occur including, potentially, nasalsymptoms (rhinorrhea, and post nasal drip), ocular symptoms(conjunctival injection, and tearing) and sinus congestion (pain orpressure around the sinuses). Other parasympathetic projections furtheraggravate the cascade of events, like the Sphenopalatine ganglionafferents that innervate the meningeal blood vessels. Activation of theparasympathetic system during a migraine attack is also accompanied by asignificant increase in the levels of Vasoactive Intestinal Polypeptide(VIP), a parasympathetic neurotransmitter which causes vasodilation andcan be measured in high concentrations during a migraine in the jugularvenous drainage.

The increased activity of the trigeminal, occipital and parasympatheticsystems just described is common to the so-called Trigeminal AutonomicCephalgias (TAC), which include Cluster headache, Paroxysmal Hemicrania,SUNCT Syndrome, and Hemicrania Continua. Cluster headaches are a primaryheadache disorder involving attacks of less than 3 hours of durationwith severe unilateral peri-orbital and temporal pain. These headachescan be associated with lacrimation, nasal congestion, rhinorrhea,conjunctival injection and a Homer's syndrome. The attacks occur indistinct clusters. Cluster headaches typically involve a series ofdisabling attacks on a daily basis lasting for months at a time. Thispattern recurs annually or biannually.

Paroxysmal hemicrania is a primary headache disorder involving frequentattacks of unilateral, peri-orbital and temporal pain typically lastingless than 30 minutes. The pain can be associated with conjunctivalinjection, lacrimation, nasal congestion, rhinorrhea, ptosis and eyelidedema.

SUNCT Syndrome is a primary headache disorder characterized by multipleattacks of unilateral, peri-orbital and temporal pain typically lastingless than 2 minutes. The pain is associated with conjunctival injection,lacrimation, nasal congestion, rhinorrhea, and eyelid edema. Thisheadache may be associated with trigeminal neuralgia.

Hemicrania Continua is a primary headache disorder characterized by astrictly unilateral headache responsive to Indomethacin. The pain isassociated with conjunctival injection, lacrimation, nasal congestion,rhinorrhea, ptosis, and eyelid edema.

The trigeminal nerve is involved in the pain sensations for all of theseheadache types, as well as headaches triggered by other pathologies. Forexample, Temporal Arteritis involves inflammation of the temporal arterywith painful palpable nodules along the artery. In addition to headachein the temporal area, Temporal Arteritis causes vision loss and jawpain.

Headaches can also be associated with ischemic stroke. In a stroke, alack of blood supply to brain tissue causes a sudden localizedneurological deficit. In a large number of affected patients, occlusionof the arteries is due to the presence of atherosclerotic plaques in thearteries supplying the brain, for example, the carotid artery and thevertebral basilar artery. The atherosclerotic plaques are oftenassociated with inflammation which further contributes to occlusion ofthe blood vessel.

Nociceptive fibers stimulated by inflammatory mediators in infectious orallergic rhinitis can also activate the trigeminal brainstem nucleus andprecipitate migraine.

TAC and migraine are difficult to treat. Numerous medications have beenused to prevent cluster and migraine headaches from occurring, whichinclude, amongst others: propranolol, timolol, divalproex sodium,topiramate, verapamil, indomethacin and amitriptyline. These medicineshave numerous side effects and patients are poorly compliant with them.In the case of TAC, indomethacin, in particular, is difficult forpatients to tolerate due to gastro-intestinal upset.

All of the headache disorders described above produce disability andbetter treatment modalities are needed.

Additionally, rhinorrhea (postnasal drip) and excessive lacrimation aredisorders in need of effective treatments. The patency of the nasalpathway is regulated by the autonomic nervous system. Sympatheticactivity decreases nasal airway resistance by constricting nasalcapacitance vessels and venous sinusoids, and parasympathetic activityproduces nasal mucus from submucosal seromucinous glands. Nasal mucus iscomposed of 96 percent water and about 3 percent mucin. Excessiveparasympathetic activity produces a copious flow of clear waterysecretions. Therapeutic efforts to decrease rhinorrhea in human haveattempted to either sever the parasympathetic nerve supply throughVidian neurectomy or chemically block the mucosal receptors foracetylcholine using short-acting, topical atropine analogs.

Recently, Botulinum toxin has been shown to be effective to treatmigraine headaches when injected in the face, cranium and neck (Binder,U.S. Pat. No. 5,714,468). Botulinum toxin is a potent polypeptideneurotoxin produced by the gram positive bacterium Clostridium botulinumwhich causes a paralytic illness in humans termed botulism. Botulinumtoxin has a light and a heavy chain. The heavy chain attaches to a cellsurface receptor and the complex is then endocytosed. After endocytosis,the light chain translocates from the endosome into the cytoplasm, whereit cleaves a segment of the SNARE protein complex responsible forvesicle fusion in the presynaptic nerve terminal. As a result, therelease of neurotransmitters from these vesicles is effectively blockedfor 3-6 months.

There are 7 immunologically distinct toxins: A, B, C1, D, E, F and G(Simpson, et al., Pharmacol. Rev., 33:155-188, 1981). These toxins bindto presynaptic membranes of target nerves and appear to work in asimilar fashion (Brin, et al., “Report of the Therapeutics andTechnology Assessment Subcommittee of the American Academy ofNeurology”, Neurology, 40:1332-1336, 1990). Botulinum toxin shows a highaffinity for cholinergic neurons. Botulinum toxin type A produces areversible, flaccid paralysis of mammalian skeletal muscle, presumablyby blocking the exocytosis of acetylcholine at peripheral, presynapticcholinergic receptors (Rabasseda, et al., Toxicon, 26:329-326, 1988).However, flaccid muscular paralysis is not necessary to achieve thereduction or prevention of migraine symptomatology. In fact, headachepain reduction may be observed at dosages of presynaptic neurotoxinwhich are lower or higher than dosages required to produce flaccidparalysis of skeletal muscle and without introduction of the neurotoxininto muscle tissue (Binder, U.S. Pat. No. 5,714,468).

Although the molecular basis for the sensation of migraine pain is notclear (Goadsby, et al., N. Eng. J. Med., 346:257-270, 2004), Botulinumtoxin might exert its analgesic effect by blocking the release ofnociceptive and inflammatory agents that are released during migraine,and not by blocking the release of acetylcholine. Because Botulinumtoxin does not act on acetylcholine directly, but on the SNARE proteincomplex that mediates vesicle fusion, the release of other moleculeswhich is also mediated by the SNARE protein complex is also affected bythe toxin (Aoki, Current Medicinal Chemistry, 11:3085-3092, 2004). Infact, studies have shown that Botulinum toxin can also block the releaseof substance P, which is associated with neurogenic inflammation andpain generation (Aoki, Current Medicinal Chemistry, 11:3085-3092, 2004),glutamate, also associated with nociception (Cui, et al., Pain,107:125-133, 2004), epinephrine, norepinephrine, and calcitoningene-related peptide (Aoki, Current Medicinal Chemistry, 11:3085-3092,2004). Botulinum toxin type A does not appear to cause degeneration ofnervous or muscular tissue and has been approved for use in certaintherapies by the U.S. Food and Drug Administration.

In addition to Botulinum toxin type A, other presynaptic neurotoxinshave also been suggested to be useful for the treatment of migraine,given the functional characteristics they share with Botulinum toxin(Binder, U.S. Pat. No. 5,714,468). One of these presynaptic neurotoxinsis Tetanus neurotoxin, which is produced by Clostridium tetani(DasGupta, et al., Biochemie, 71:1193-1200, 1989), and shows significantsequence homology with serotypes A and E of Botulinum toxin. Inparticular, fragment Ibc of the Tetanus toxin, which is obtained bypeptide digestion of the toxin, appears to act peripherally to produceflaccid paralysis (Fedinic, et al., Boll.lst. Sieroter Milan, 64: 35-41,1985; and, Gawade, et al., Brain Res., 334:139-46, 1985).

Staphylococcal alpha-toxin has also been suggested for therapeutic use.This toxin stimulates the production in the brain of muscle-relaxingfactor (MRF), which results in reversible, flaccid paralysis of skeletalmuscle (Harshman, et al., Infect. Immun., 62:421-425, 1994).Staphylococcal alpha-toxin may function similarly to Botulinum toxin.

Other toxins which cause reversible, flaccid paralysis are theacylpolyamine toxins, which are anticholinergic, presynaptic neurotoxinsproduced in the venom of many invertebrates (Herold, et al.,Anesthesiology, 77:507-512, 1992). For example, toxins AR636 and AG489from spiders Argiope aurantia and Agelenopsis aperta lead to motorinhibition at a dosage of 2 micrograms and sensory inhibition at 7micrograms.

Since the use of presynaptic neurotoxins to treat migraines wasinitially implemented by administering the toxins in the face, craniumand/or neck (Binder, U.S. Pat. No. 5,714,468), the hypothesis about thephysiological changes underlying migraine has been significantlydeveloped. The present invention provides an improvement in thetherapeutic and preventive use of Botulinum toxin, among otherpresynaptic neurotoxins, to treat migraines, TAC and other headachesassociated with vascular conditions by using a new method to administerthese neurotoxins. The improvement is based on the recent theory thathas emerged about the pathophysiological changes triggering theseheadaches, which involves the trigeminal, occipital and parasympatheticsystems and therefore affects the administration sites of the toxins.

SUMMARY OF THE INVENTION

There is a need in the medical field to provide an effective therapeuticand prophylactic treatment for migraines, TAC, and other headachesassociated with vascular conditions. The present invention provides amethod for reducing or preventing symptoms and in particular painrelated to migraines, TAC, and other headaches associated with vascularconditions in mammals, particularly humans. Specifically, the inventionprovides an improvement for current methods to treat and prevent theseheadaches with presynaptic neurotoxins. More specifically, the presentinvention relates to administering a therapeutically effective amount ofa pharmaceutically safe presynaptic neurotoxin, to the sphenopalatineganglion of a mammal.

The presynaptic neurotoxins of the invention will be those presynapticneurotoxins that produce reversible, localized paralysis of musculaturewhen administered to a mammal (although to practice the invention suchparalysis is not needed) and do not cause degeneration of muscle ornervous tissue. Botulinum toxin, and in particular, Botulinum toxin typeA is a preferred presynaptic neurotoxin of the invention.

In one embodiment, a method for reduction of headache pain in a mammalis provided comprising: administering by injection to the sphenopalatineganglion, in a pharmaceutically safe form to a mammal, a therapeuticallyeffective amount of a presynaptic neurotoxin. In one embodiment thepresynaptic neurotoxin is a botulinum toxin including, but not limitedto botulinum toxin types A, B, C, D, E, F and G. In another embodiment,the presynaptic neurotoxin is Botulinum toxin type A.

In another embodiment, the headache pain is associated with a headachefrom the group consisting of migraine, trigeminal autonomic cephalgiaand headache caused by a vascular condition.

In yet another embodiment of the methods, the administering stepcomprises the steps of identifying an injection site midway between thetragus of the ear and the outer cantus of the eye; inserting a syringeat an angle of about 50-70 degrees relative to the vertical plane of theface; stopping the forward motion of the syringe upon reaching themaxillary bone; injecting the presynaptic neurotoxin at thesphenopalatine ganglion; and withdrawing the syringe.

In one embodiment, the administering step is performed bilaterally. Inanother embodiment, the administering step is performed unilaterally.

In another embodiment, the presynaptic neurotoxin is injected a discretemanner at a plurality of locations adjacent to the sphenopalatineganglion.

In one embodiment disclosed herein, a method for reduction of headachepain in a mammal is provided comprising: administering by injection tothe sphenopalatine ganglion, in a pharmaceutically safe form to amammal, a therapeutically effective amount of Botulinum toxin type A.

In another embodiment, a method for reduction of rhinorrhea in a mammalis provided comprising administering by injection to a sphenopalatineganglion, in a pharmaceutically safe form to a mammal, a therapeuticallyeffective amount of botulinum toxin, selected from the group consistingof botulinum toxin types A, B, C, D, E, F and G. “Botulinum toxin” meansa botulinum neurotoxin as either pure toxin or complex, and excludesbotulinum toxins which are not neurotoxins such as the cytotoxicbotulinum toxins C₂ and C₃.

In another embodiment, a method for reduction of lacrimation in a mammalis provided comprising administering by injection to a sphenopalatineganglion, in a pharmaceutically safe form to a mammal, a therapeuticallyeffective amount of Botulinum toxin type A.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts headache pain pathways, illustrating the input and outputpathways of the trigeminal nucleus caudalis in the brainstem.

FIG. 2 depicts the trigeminal and parasympathetic network involved inheadache pain, from and into the brainstem.

FIG. 3 depicts the neural innervation of the cranial circulation,illustrating the trigeminal nociceptive input from the internal carotidto the trigeminal nucleus caudalis of the brainstem, and the connectionto the parasympathetic system through the superior salivatory nucleus.The parasympathetic system feeds back into the internal and externalcarotids, which connect with the temporal and occipital arteries.

FIG. 4 depicts an illustrated lateral view of a human head showing theconnection between the external carotid and the superficial temporal andoccipital arteries. FIG. 4 has been adapted from Agur, A. M. R. andDalley II, A. F. (2005) Atlas of Anatomy 11.sup.th Ed., LippincottWilliams & Wilkins, Philadelphia. Refer to pages 316, 317, 600, 601 and736 of the original reference for a detailed view of the anatomy.

FIG. 5 depicts mapping of the anterior temporal fossa.

FIG. 6 depicts injection of a postsynaptic neurotoxin by insertion of aneedle at angle α.

FIG. 7 depicts one embodiment of the disclosed method whereindiscontinuous discreet injections of postsynaptic neurotoxin areadministered to or around the sphenopalatine ganglion.

FIG. 8 depicts the withdrawal of the needle along an injection track.

DETAILED DESCRIPTION OF THE INVENTION

The anatomical and physiological theory of migraine, trigeminalautonomic cephalgias (TAC), and other headaches associated with vascularconditions, as described in the Background section, suggests thatblockade of the release of nociceptive and inflammatory agents triggeredby the hyperactivation of the trigeminal, occipital and parasympatheticsystems involved in the development of these headaches should provide aneffective therapeutic and/or prophylactic treatment. As depicted inFIGS. 1 and 2, some of the anatomical pathways involved in thedevelopment of these headaches are intracranial; therefore, specificblockade of the intracranial pathways involved by non-invasive means isnot feasible. However, some of the pathways affected are locatedextracranially under the surface of the skin or intranasally, and aretherefore accessible to treatment. Some examples of these pathwaysinclude the temporal arteries and muscles (FIGS. 1 and 4), the nasalglands and mucosa (FIG. 2) and the occipital nerve and artery (FIG. 4).The current disclosure relates to providing a method for blocking therelease of nociceptive and inflammatory agents triggered by thehyperactivation of the trigeminal, occipital and parasympathetic fibersthat is increased during migraine, TAC or other headaches associatedwith vascular conditions.

Furthermore, the current disclosure provides methods for treatingrhinorrhea or excessive lacrimation by injection of a presynapticneurotoxin to the sphenopalatine ganglion.

The therapeutic modality used to treat and/or prevent the conditionsdescribed in this disclosure is the use of presynaptic neurotoxins.“Presynaptic neurotoxin” as used herein refers to those neurotoxins andtheir derivatives which are known to produce localized, reversibleflaccid paralysis of musculature in mammals which does not result indegeneration of muscle or nervous tissue. However, as stated earlier,flaccid muscular paralysis which the disclosed presynaptic neurotoxinswill produce is not necessary to achieve the reduction or prevention ofheadache symptomatology with the disclosed methods.

In one embodiment, the presynaptic neurotoxin of the invention isBotulinum toxin. In one useful embodiment of the invention, thepresynaptic neurotoxin is Botulinum toxin type A. Botulinum toxin type Ais presently supplied and commercially available as “BOTOX®” byAllergan, Inc. of Irvine, Calif., and as “Dysport®” by Ipsen, ofBerkshire, UK. In another embodiment of the invention, the presynapticneurotoxin is Botulinum toxin B. Botulinum toxin B is commercialized as“Neurobloc®”/“Myobloc” by Solstice Neuroscience, Inc, of San Francisco,Calif. A pentavalent toxoid of all eight known Botulinum serotypes isalso available as an investigational drug from the U.S. Center forDisease Control in Atlanta, Ga. The Botulinum A toxin preparations aremost preferred for their known safety and efficacy. BOTOX® has also beenused to treat, among other things, cervical dystonia, brow furrows,blepharospasm, strabismus, and hyperhidrosis.

Tetanus toxins are also commercially available for use as vaccines.Since the Ibc fragment of the Tetanus toxin is likely to act in asimilar fashion to Botulinum toxin, as suggested earlier, a furtherembodiment of the present methods will comprise the use ofpharmaceutically safe forms of the Ibc fragment of the Tetanus toxinrather than the intact form of the toxin.

Obtaining the presynaptic neurotoxins, including the Botulinum andTetanus toxins, in a pharmaceutically safe form and therapeuticallyeffective amount should be known or easily determined by those ofordinary skill in the art. The presynaptic neurotoxins should preferablybe in a nonteratogenic form that does not trigger a detectable immuneresponse. Pharmaceutical safety will be dose-dependent for most of thepresynaptic neurotoxins, in such a way that fairly low doses of toxinwill be “safe” as compared to doses known to produce disease.

The presynaptic neurotoxins will be preferably administered as acomposition in a pharmaceutically suitable carrier. For this purpose,presynaptic neurotoxin compositions will be prepared for administrationby combining a toxin of the desired degree of purity withphysiologically suitable sterile carriers. These carriers will notproduce toxic responses in recipients at the doses and concentrationsused. In a preferred embodiment, the preparation of such compositionstypically involves mixing the presynaptic neurotoxin with buffers,antioxidants such as ascorbic acid, low molecular weight (less thanabout 10 residues) polypeptides, proteins, amino acids, carbohydratesincluding glucose or dextrins, chelating agents such as EDTA,glutathione and other stabilizers and excipients. These compositions canalso be lyophilized and will be pharmaceutically acceptable; i.e.,appropriately prepared and approved for use in the desired application.

To facilitate administration, the presynaptic neurotoxins can beformulated in unit dosage form. The presynaptic neurotoxins may besupplied, for example, as a sterile solution or as a lyophilized powderin a vial.

In general, the amount of presynaptic neurotoxins used for treatmentwill be determined by the age, gender, presenting condition and weightof the patient, in consideration of the potency of the presynapticneurotoxin. The potency of a toxin is expressed as a multiple of theLD₅₀ value for a reference mammal. One “unit” of toxin is the amount oftoxin that kills 50% of a group of mammals that were disease-free priorto inoculation with the toxin. For example, one unit of Botulinum toxinis defined as the LD₅₀ upon intraperitoneal injection into female SwissWebster mice weighing 18-20 grams each. One nanogram of the commerciallyavailable Botulinum toxin type A typically contains about 40 mouseunits. The potency in humans of the Botulinum toxin type A productcurrently supplied by Allergan, Inc. as “BOTOX®” is estimated to beabout LD₅₀=2,730 units.

Assuming an approximate potency of LD₅₀=2,730 units, the presynapticneurotoxin can be administered in a dose of up to about 1,000 units;however, dosages of as low as about 2.5 to 5 units will have therapeuticefficacy. Dosages between 2.5 or 5 units and as high as 250 units willbe normally used, and in one embodiment, individual dosages will be ofabout 15-30 units. Typically, the presynaptic neurotoxin will beadministered as a composition at a dosage that is proportionallyequivalent to a range of between 1 cc-5 cc/100 units, which translate to100 units/cc-20 units/cc. Adjustment of these dosages depending on thegreater or lesser potency of the presynaptic neurotoxins and factorsidentified above should be easily determined by those of ordinary skillin the art.

In one embodiment, the dosage used will be the lowest one which is stilltherapeutically effective (i.e., the dosage which results in detectionby the patient of a reduction in the occurrence and/or magnitude ofheadache pain experienced by the patient, even though other symptomsassociated with the pain, such as the premonitory aura, may persist).The patient's sensitivity to, and tolerance of, the presynapticneurotoxin can be determined in the initial treatment by administering alow dosage at one site. Additional administrations of the same ordifferent dosages can be provided as needed.

The injections will be repeated as necessary. As a general guideline,Botulinum toxin type A administered into or near muscle tissue has beenobserved to produce flaccid paralysis at target site muscles for up toabout 3 to 6 months. However, increased efficacy of the treatment usingBotulinum toxin type A is expected to happen when the toxin isadministered according to the disclosed method at about 3 monthintervals.

In one embodiment, commercially available BOTOX® can be reconstitutedwith sterile non-preserved saline prior to injection. Each vial ofBOTOX® contains about 100 units of clostridium Botulinum toxin type Apurified neurotoxin complex. Dilutions will vary depending upon thecommercial preparation.

The technique of administrating presynaptic neurotoxins to modulate theparasympathetic, trigeminal and occipital nerve responses involved inTAC, migraine and other headaches associated with vascular conditions,involves distributing the presynaptic neurotoxins around the nerveendings involved. Because a high concentration of the trigeminal nerveendings are wrapped around the arteries, injections of presynapticneurotoxins along the trajectory of the temporal extracranial artery isan effective way of administering presynaptic neurotoxins, and inparticular Botulinum toxins, for the treatment of migraine, TAC andother headaches. The same rationale applies to the occipital nerveendings along the extracranial occipital artery. This method helps tolocate the synaptic terminals of the targeted nerves, which allows forthe maximum adherence of presynaptic neurotoxins to the pain generatingnerves involved in headache disorders.

In one embodiment, the presynaptic neurotoxins are administered by wayof injection. However, in other embodiments, the presynaptic neurotoxinsmay be administered topically. In general, the preparation of thepresynaptic neurotoxin solution for topical delivery may be the same asthat which is injected. However, in other embodiments, the presynapticneurotoxin may be applied topically via a carrier known to those ofskill in the art. The solutions can then be administered by severalmeans, like for example, a pledget of cotton or cotton tippedapplicator, a dropper or a spray in the case of a solution, or a spatulain the case of a cream. These topical methods of application may be usedwherever trigeminal, occipital or parasympathetic nerve endings can beaccessed efficiently by such application. The solution containing thepresynaptic neurotoxins can be administered topically to the epidermisthrough these means and the presynaptic neurotoxins can then bedistributed through the epidermis by transdermal carrier systems. Aswould be obvious to one of skill in the art, topical administration maynot be as effective as administration via injection depending on, forexample, the patient, the severity of the symptoms and access to thetrigeminal, occipital and parasympathetic nerves.

The disclosed presynaptic neurotoxins can be administered with orwithout anesthesia or application of a topical anesthetic.

In one embodiment, the target administration sites for the currentmethods are the extracranial and intranasal trigeminal nerve endings andparasympathetic nerve endings of the nasal mucosa, the extracranialtemporal trigeminal endings and the extracranial occipital nerveendings. The parasympathetic nerve endings in the nasal mucosa, alsosituated around the lacrimal glands are illustrated in FIG. 2. Thetrigeminal nerve endings are situated around the temporal artery (FIG.4) and temporal muscle, as shown in FIG. 1, and the occipital nerveendings are located around the occipital arteries (FIG. 4) via cervicalnerve roots that connect with the trigeminal spinal nucleus. Presynapticneurotoxins injected in these locations every 3-6 months produce atherapeutic beneficial effect on migraine, TAC and other headachesassociated with vascular conditions.

Nasal Administration

To target the intranasal trigeminal nerve endings and parasympatheticnerve endings in the nasal mucosa, the method of administration involvesinfiltrating the upper respiratory tract (nasal mucosa and turbinates)with a presynaptic neurotoxin diluted with a suitable solution such assaline. There is a coalescence of nerve fibers within the upper regionof the nose (intranasally) near the cribriform plate and above thesuperior turbinate. It is also known anatomically that the inferiorturbinate, which is the most responsive organ in the nose, is formed ofbone and mucosa composed of vascular lakes that provide the basis fornasal sprays and topical medications administered intranasally whichprovide for rapid local transmucosal absorption.

In a preferred embodiment, Botulinum toxin Type A (BOTOX®) is used, andeach nostril is infiltrated with 5 to 10 units using a solution of 100units of BOTOX® diluted with 4 cc of normal saline. The infiltration inthis preferred embodiment is performed by injection using a 30 gaugeneedle. Intranasal injections are given in each nostril using endoscopicapplication, or a needle palpation technique. The needle is insertedthrough the nostril. Lateral and medial mucosal infiltration isperformed either through finger palpation and guidance or through directvisualization using a nasal speculum and an external light source or viaendoscopic guidance.

In another embodiment, BOTOX® is used and it is administered in theregion of the external nares using 5 to 10 units using a solution of 100units of BOTOX® diluted with 4 cc of normal saline. The infiltration inthis preferred embodiment is performed by injection using a 30 gaugeneedle. If necessary, BOTOX® can be also administered in thedistribution of the infraorbital nerve.

In another embodiment, infiltration of the presynaptic neurotoxins inthe upper respiratory tract will be done by topical administration tothe intranasal mucosa (either alone or with a carrier substrate) which,because of its anatomical proximity to the end terminals of thetrigeminal nerve or the sphenopalatine ganglion that innervate the nose,will have a direct effect on the alleviation of headache pain. In aparticular embodiment, the presynaptic neurotoxin solution, with orwithout a carrier, will be delivered with a cotton pledget or a dropperand spread along the targeted area. In another embodiment, thepresynaptic neurotoxin solution, with or without a carrier, will bedelivered in the form of an emollient, cream or solution, and spreadover the epidermis of the targeted area. In yet a different embodiment,the presynaptic neurotoxin solution, with or without a carrier, will bedelivered in the form of a spray. Other embodiments may use alternativemethods of topical delivery known to those of skill in the art.

Example 1

A 48 yr. old female patient with chronic migraine associated withrhinorrhea and cervical dystonia was treated with the disclosedintranasal method. Her migraines involved the left hemicranium and wereassociated with left rhinorrhea. Initial Botulinum toxin treatment usingmigraine and cervical dystonia protocols improved her headaches, but didnot completely abort them, while the rhinorrhea persisted. The patientwas treated with intranasal injections of BOTOX® 2.5 units (4 ccdilution) four times on the left side only, using the needle palpationapproach. There was no change in the shape of the nose or the cartilagebase. The discomfort was minimal and the bleeding was not excessive. Twoweeks after the treatment, both the rhinorrhea and the headache wereresolved.

Temporal Administration

To target the extracranial trigeminal nerve endings in the temporalregion, the extracranial temporal artery is palpated and the skin ismarked where the artery's pulsations are felt. The area is theninfiltrated with presynaptic neurotoxins diluted in a suitable solutionsuch as normal saline along the course of the artery. In a preferredembodiment, the presynaptic neurotoxin used is Botulinum toxin type A,and the total dose given per artery is 20 units using a solution of 100units of BOTOX® diluted with 2-4 cc of normal saline. The infiltrationin this preferred embodiment is performed by injection with a 30 gaugeneedle.

In the case of headaches stemming from Temporal Arteritis, presynapticneurotoxins are infiltrated around the temporal artery using a similartechnique to that just described. In one embodiment, Botulinum toxinwill be administered by injection.

In another embodiment, infiltration of the presynaptic neurotoxins alongthe temporal artery will be done by topical administration, in a similarway as that described for the intranasal area. In a particularembodiment, the presynaptic neurotoxin solution will contain atransdermal carrier. In a different embodiment, the presynapticneurotoxin solution will be delivered in the form of a spray along thetemporal artery, and care will be taken to shield the non-targeted areasof the scalp.

Occipital Administration

The occipital artery can be treated in a similar fashion. The artery islocated using the following landmarks: the midpoint between the nuchalridge (inion) and the mastoid process is found; light palpation is usedto feel the occipital artery's pulse. The hair is separated and the skinis marked along the course of the artery. Presynaptic neurotoxinsdiluted in normal saline or other suitable solution are infiltratedaround each artery. In a preferred embodiment, 20 units of BOTOX® individed doses are infiltrated around each artery using a solution of 100units of BOTOX® diluted with 2-4 cc of normal saline. The infiltrationin this preferred embodiment is performed by injection with a 30 gaugeneedle.

In another embodiment, infiltration of the presynaptic neurotoxins alongthe occipital artery will be done by topical administration, in the sameway described earlier for the temporal administration.

Depending on the condition of each patient, the presynaptic neurotoxinswill be administered to one of the sites just described, or to multiplesites. In one embodiment, there are multiple administration sites. In aparticular preferred embodiment, the doses ranging between 25 units and250 units are equally divided among the different administration sites.One of skill in the art should readily ascertain how to adjust thenumber of administration sites and dosages based on individual profilesof weight, gender, age, condition severity and symptoms.

Administration to the Sphenopalatine Ganglion

In one embodiment, a direct sphenopalatine administration of presynapticneurotoxins can be used, which in a preferred embodiment will beBotulinum toxins, and in particular, Botulinum toxin type A. In anotherembodiment, this treatment may follow prior treatments in which thepresynaptic neurotoxin had been administered at any of the foregoingsites without sufficient results. In another embodiment, this treatmentis the sole treatment administered to the patient.

Migraine and TAC involve increased activity of the trigeminal nerve andits brainstem nucleus, the trigeminal nucleus caudalis (TNC).Interneurons connect the TNC to the solitary nucleus in the brainstem.The solitary nucleus projects to the sphenopalatine ganglion whichsupplies intracranial blood vessels and the nasal mucosa. Increasedactivity in the sphenopalatine ganglion leads to dilation of bloodvessels which may contribute to the throbbing component of the headacheand may also be responsible for the nasal symptoms associated withmigraine.

The sphenopalatine ganglion, the largest of the sympathetic ganglionassociated with the branches of the trigeminal nerve, is deeply placedin the pterygopalatine fossa, close to the sphenopalatine foramen. It istriangular or heart shaped, of a reddish-gray color, and is situatedjust below the maxillary nerve as it crosses the fossa. It receives asensory, a motor and a sympathetic root. The sensory root is derivedfrom two sphenopalatine branches of the maxillary nerve; their fibers,for the most part, pass directly into the palatine nerves. A few of thefibers, however, enter the ganglion, constituting its sensory root. Themotor root is derived from the nervus intermedius through the greatersuperficial petrosal nerve and consists, in part, of sympatheticefferent (preganglionic) fibers from the medulla. In the sphenopalatineganglion, they form synapses with neurons whose postganglionic axons,vasodilator and secretory fibers, are distributed with the deep branchesof the trigeminal to the mucous membrane of the nose, soft palate,tonsils, uvula, roof of the mouth, upper lip and gums, and to the upperpart of the pharynx. The sympathetic root is derived from the carotidplexus through the deep petrosal nerve. These two nerves join to formthe nerve of the pterygoid canal before their entrance into theganglion.

Botulinum toxins generally bind to nerve endings close to theirsynapses, but may penetrate unmyelinated nerves, and even ganglia, ifdelivered at high dose in close proximity to these structures.Sphenopalatine nerve blocks have been used to treat migraines byinserting nasal swabs soaked in a local anesthetic into the posteriornares and allowed to diffuse to the sphenopalatine ganglion.

The present disclosure provides alternative methods for delivery ofpresynaptic neurotoxins to the sphenopalatine ganglion comprisinginjection of the neurotoxins into the vicinity of the sphenopalatineganglion as depicted in FIGS. 5-8.

In one embodiment, a patient in need of treatment for a headachedisorder is examined by careful palpation of the skull. The anteriortemporal fossa 102 is identified at a position halfway between thetragus of the ear 104 and the outer cantus of the eye 106. The injectionsite 108 is identified (FIG. 5) at the anterior temporal fossa 102.

In one instance, a syringe 110 containing a concentrated solution of thepresynaptic neurotoxin, such as a botulinum toxin type A, and 1.5 inch27 gauge needle 112 are used to prevent substantial diffusion of theneurotoxin from the treatment site. A concentrated solution of botulinumtoxin is preferably used, such as, for example and in the case ofutilizing BOTOX® (botulinum toxin type A), 1 cc of normal unpreservedsaline per 100 unit vial of BOTOX®. In additional embodiments, fromabout 2 cc to 4 cc dilutions per 100 units of BOTOX® are suitable.

In various administration methods, needles of various sizes can beutilized, such as, for example, about 1.5 to about 2 inches long and of30, 27 or even 25 gauge can be used. Preferably, the needle selected isat least about 1 inch long.

The needle is inserted at injection site 108 through the subcutaneoustissue, through the temporalis muscle, angling forwards at an angle α.Angle α is in the range of about 50-70 degrees relative to a verticalplane alongside the head of the patient, substantially parallel to thesagittal plane, such that the needle's entry path is behind thezygomatic arch. The needle does not penetrate the periosteum. The needleis preferably inserted to its full length (although not necessarily, asdependant upon needle length and patient anatomy, of course), until themaxillary bone is reached and the syringe is moved forward (to move theneedle dorsally). The angle of this forward movement is in the range ofabout 10-40 degrees. The needle is then slowly retracted to position 114at which time injection of presynaptic neurotoxin is administered (FIGS.7 and 8). In one embodiment of the disclosed methods, the toxin solutionis injected in the area of the sphenopalatine ganglion (FIG. 7). Uponinjection of the desired volume of presynaptic neurotoxin, the needle iswithdrawn (FIG. 8). While the sphenopalatine ganglion is describedherein, administration to other ganglion in order to interfere withimpulse transmission, as described herein, is also contemplated.

The injections can administered unilaterally or bilaterally, based uponthe location of the headache.

Example 2

A female patient presents with chronic migraines. Her migraines involvedthe right hemicranium. The patient is treated with a sphenopalatineganglion targeted injection of BOTOX® of about 100 units (in a 1 ccdilution) in a continuous injection method on the right side only, usingthe disclosed technique, to distribute the toxin around thesphenopalatine ganglion (thus minimizing/avoiding administration oftoxin to the temporalis muscle). The discomfort is minimal and thebleeding is not excessive. The patient remains upright (e.g.substantially vertical) after toxin administration (from about 15 min to3 hours, more preferably from about 1 to about 3 hours and mostpreferably from about 2 to about 3 hours), to allow toxin to remainconcentrated at the sphenopalatine ganglion and not be distributedthroughout the temporalis muscle. Two weeks after the treatment, theheadache is resolved.

Example 3

A male patient presents with bilateral cluster headaches. The patient istreated with bilateral sphenopalatine ganglion injections of BOTOX®(botulinum toxin type A at 50 units per side, (in a 1 cc dilution, i.e.50 units per/cc/side) at a plurality of sites along the injection needletrack, around the sphenopalatine ganglion (thus minimizing/avoidingadministration of toxin to the temporalis muscle). The discomfort isminimal and the bleeding is not excessive. The patient remains upright(e.g. substantially vertical) after toxin administration (from about 15min to 3 hours, more preferably from about 1 to about 3 hours and mostpreferably from about 2 to about 3 hours), to allow toxin to remainconcentrated at the sphenopalatine ganglion and not be distributedthroughout the temporalis muscle, as above. Two weeks after thetreatment, the headache is resolved.

Example 4

A female patient presents with rhinorrhea. The patient is treated withunilateral or bilateral sphenopalatine ganglion injections of BOTOX®(botulinum toxin type A at 50 units per side, (in a 1 cc dilution, i.e.50 units per/cc/side) at a plurality of sites along the injection needletrack, around the sphenopalatine ganglion (thus minimizing/avoidingadministration of toxin to the temporalis muscle). The discomfort isminimal and the bleeding is not excessive. The patient remains upright(e.g. substantially vertical) after toxin administration (from about 15min to 3 hours, more preferably from about 1 to about 3 hours and mostpreferably from about 2 to about 3 hours), to allow toxin to remainconcentrated at the sphenopalatine ganglion and not be distributedthroughout the temporalis muscle, as above. The rhinorrhea is resolvedin 24 to 72 hours.

Example 5

A male, age 65, with excessive lacrimation is treated with unilateral orbilateral sphenopalatine ganglion injections of BOTOX® (botulinum toxintype A at 50 units per side (in a 1 cc dilution, i.e. 50 unitsper/cc/side) at a plurality of sites along the injection needle track,around the sphenopalatine ganglion (thus minimizing/avoidingadministration of toxin to the temporalis muscle). The discomfort isminimal and the bleeding is not excessive. The patient remains upright(e.g. substantially vertical) after toxin administration (from about 15min to 3 hours, more preferably from about 1 to about 3 hours and mostpreferably from about 2 to about 3 hours), to allow toxin to remainconcentrated at the sphenopalatine ganglion and not be distributedthroughout the temporalis muscle, as above. All symptoms would bereduced or eliminated with toxin therapy in about 1-7 days. Durationwould be weeks to several months.

Other Administration Sites

In the case of atherosclerotic disease, presynaptic neurotoxins,preferably Botulinum toxins can be injected directly into the plaque viaan intra-arterial catheter. Botulinum toxins will be of benefit as theseplaques produce inflammation in the blood vessel wall in response tocholesterol deposits. This inflammation further compromises the diameterof the lumen of the blood vessel. Botulinum toxins will focally reducethis inflammation for 3 to 6 months.

For the administration of presynaptic neurotoxins by injection, dilutiondependent syringes with gauging for units rather than volume injectedare recommended. This will ensure that the volume injected contains thedesired amount of units, since the volume injected will depend on howthe original concentration of the presynaptic neurotoxin was dilutedwhen reconstituted. For example, in the embodiment in which 100 units ofBotulinum toxin type A are reconstituted in 4 cc of normal saline, aspecific syringe with demarcations at 0.1 cc of 2.5 units, and at 0.2 ccof 5 units will be used. In another embodiment in which 100 units ofBotulinum toxin type A are reconstituted in 1 cc of normal saline, thesyringe with demarcations at 0.1 cc of 10 units; and at 0.2 cc of 20units will be used. These delivery tools allow for accurate delivery andrecording of the dose given.

The invention having been fully described, examples illustrating itspractice should not, however, be considered to limit the scope of theinvention.

Unless otherwise indicated, all numbers expressing quantities ofingredients, properties such as molecular weight, reaction conditions,and so forth used in the specification and claims are to be understoodas being modified in all instances by the term “about.” Accordingly,unless indicated to the contrary, the numerical parameters set forth inthe specification and attached claims are approximations that may varydepending upon the desired properties sought to be obtained by thepresent invention. At the very least, and not as an attempt to limit theapplication of the doctrine of equivalents to the scope of the claims,each numerical parameter should at least be construed in light of thenumber of reported significant digits and by applying ordinary roundingtechniques. Notwithstanding that the numerical ranges and parameterssetting forth the broad scope of the invention are approximations, thenumerical values set forth in the specific examples are reported asprecisely as possible. Any numerical value, however, inherently containscertain errors necessarily resulting from the standard deviation foundin their respective testing measurements.

The terms “a,” “an,” “the” and similar referents used in the context ofdescribing the invention (especially in the context of the followingclaims) are to be construed to cover both the singular and the plural,unless otherwise indicated herein or clearly contradicted by context.Recitation of ranges of values herein is merely intended to serve as ashorthand method of referring individually to each separate valuefalling within the range. Unless otherwise indicated herein, eachindividual value is incorporated into the specification as if it wereindividually recited herein. All methods described herein can beperformed in any suitable order unless otherwise indicated herein orotherwise clearly contradicted by context. The use of any and allexamples, or exemplary language (e.g., “such as”) provided herein isintended merely to better illuminate the invention and does not pose alimitation on the scope of the invention otherwise claimed. No languagein the specification should be construed as indicating any non-claimedelement essential to the practice of the invention.

Groupings of alternative elements or embodiments of the inventiondisclosed herein are not to be construed as limitations. Each groupmember may be referred to and claimed individually or in any combinationwith other members of the group or other elements found herein. It isanticipated that one or more members of a group may be included in, ordeleted from, a group for reasons of convenience and/or patentability.When any such inclusion or deletion occurs, the specification is deemedto contain the group as modified thus fulfilling the written descriptionof all Markush groups used in the appended claims.

Certain embodiments of this invention are described herein, includingthe best mode known to the inventors for carrying out the invention. Ofcourse, variations on these described embodiments will become apparentto those of ordinary skill in the art upon reading the foregoingdescription. The inventor expects skilled artisans to employ suchvariations as appropriate, and the inventors intend for the invention tobe practiced otherwise than specifically described herein. Accordingly,this invention includes all modifications and equivalents of the subjectmatter recited in the claims appended hereto as permitted by applicablelaw. Moreover, any combination of the above-described elements in allpossible variations thereof is encompassed by the invention unlessotherwise indicated herein or otherwise clearly contradicted by context.

Furthermore, numerous references have been made to patents and printedpublications throughout this specification. Each of the above-citedreferences and printed publications are individually incorporated hereinby reference in their entirety.

In closing, it is to be understood that the embodiments of the inventiondisclosed herein are illustrative of the principles of the presentinvention. Other modifications that may be employed are within the scopeof the invention. Thus, by way of example, but not of limitation,alternative configurations of the present invention may be utilized inaccordance with the teachings herein. Accordingly, the present inventionis not limited to that precisely as shown and described.

I claim:
 1. A method for reduction of pain associated with a headache ina mammal in need thereof, comprising the step of administering atherapeutically effective amount of a botulinum toxin to occipital nerveendings along the extracranial occipital artery, thereby effectingreduction of headache pain in the mammal in need thereof.
 2. The methodof claim 1, wherein the botulinum toxin is administered by injection. 3.The method of claim 1, wherein the botulinum toxin is administeredtopically.
 4. The method of claim 1, wherein the botulinum toxin isbotulinum toxin type A.
 5. The method of claim 1, wherein the headacheis selected from the group consisting of migraine, trigeminal autonomiccephalgia and headache caused by a vascular condition.
 6. The method ofclaim 1, further comprising the step of locating the extracranialoccipital artery.
 7. The method of claim 6, wherein the step of locatingthe extracranial occipital artery utilizes palpation.
 8. A method forreduction of a pain associated with a headache in a mammal in needthereof, the method comprising the steps of: determining the projectionof an extracranial occipital artery; infiltrating an area around theextracranial occipital artery with a therapeutically effective amount ofa botulinum toxin; and administering botulinum toxin to occipital nerveendings, thereby reducing the pain associated with the headache.
 9. Themethod of claim 8, wherein the determining step utilizes palpation todetermine the projection of the extracranial artery.
 10. The method ofclaim 8, wherein the step of infiltrating the area around theextracranial occipital artery utilizes injection or topicaladministration of botulinum toxin.
 11. The method of claim 10, whereinthe botulinum toxin is administered by injection.
 12. The method ofclaim 10, wherein the botulinum toxin is selected from the groupconsisting of botulinum toxin type A, B, C₁, D, E, F and G.
 13. Themethod of claim 10, wherein the botulinum toxin is botulinum toxin typeA.
 14. The method of claim 8, wherein the infiltrating and administeringsteps are performed unilaterally or bilaterally.
 15. The method of claim8, wherein the headache is selected from the group consisting ofmigraine, trigeminal autonomic cephalgia and headache caused by avascular condition.
 16. The method of claim 8, wherein the botulinumtoxin is administered topically.
 17. A method for reduction of painassociated with a headache in a mammal in need thereof, comprising thestep of administering a therapeutically effective amount of a botulinumtoxin to a trigeminal, parasympathetic, occipital nerve endings orcombinations thereof, thereby effecting reduction of headache pain inthe mammal in need thereof.
 18. The method of claim 17, wherein thebotulinum toxin is administered topically.
 19. The method of claim 17,wherein the botulinum toxin is administered by injection.